7.3 The Action Potential
The functions of the nervous system—sensation, integration, and response—depend on the functions of the neurons underlying these pathways. To understand how neurons can communicate, it is necessary to describe the role of an excitable membrane in generating these signals. The basis of this communication is the action potential, which demonstrates how changes in the membrane can constitute a signal.
Electrically Active Cell Membranes
Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane. The cell membrane is primarily responsible for regulating what can cross the membrane and what stays on only one side. The cell membrane is a phospholipid bilayer, so only substances that can pass directly through the hydrophobic core can diffuse through unaided. Charged particles, which are hydrophilic, cannot pass through the cell membrane without assistance. Transmembrane proteins, specifically channel proteins, make this possible. Several passive transport channels, as well as active transport pumps, are necessary to generate a transmembrane potential and an action potential.
For example
For skeletal muscles to contract, based on excitation–contraction coupling, requires input from a neuron. Both cells make use of the cell membrane to regulate ion movement between the extracellular fluid and cytosol.
Of special interest is the carrier protein referred to as the sodium/potassium pump that moves sodium ions (Na+) out of a cell and potassium ions (K+) into a cell, thus regulating ion concentration on both sides of the cell membrane.
The sodium/potassium pump requires energy in the form of adenosine triphosphate (ATP), so it is also referred to as an ATPase. As was explained in the cell chapter, the concentration of Na+ is higher outside the cell than inside, and the concentration of K+ is higher inside the cell than outside. That means that this pump is moving the ions against the concentration gradients for sodium and potassium, which is why it requires energy. In fact, the pump basically maintains those concentration gradients.
Ion channels are pores that allow specific charged particles to cross the membrane in response to an existing concentration gradient. Proteins can span the cell membrane, including its hydrophobic core, and can interact with the charge of ions because of the varied properties of amino acids found within specific domains or regions of the protein channel. Hydrophobic amino acids are found in the domains that are apposed to the hydrocarbon tails of the phospholipids. Hydrophilic amino acids are exposed to the fluid environments of the extracellular fluid and cytosol. Additionally, the ions will interact with the hydrophilic amino acids, which will be selective for the charge of the ion. Channels for cations (positive ions) will have negatively charged side chains in the pore. Channels for anions (negative ions) will have positively charged side chains in the pore. This is called electrochemical exclusion, meaning that the channel pore is charge-specific.
Ion channels can also be specified by the diameter of the pore. The distance between the amino acids will be specific for the diameter of the ion when it dissociates from the water molecules surrounding it. Because of the surrounding water molecules, larger pores are not ideal for smaller ions because the water molecules will interact, by hydrogen bonds, more readily than the amino acid side chains. This is called size exclusion. Some ion channels are selective for charge but not necessarily for size, and thus are called a nonspecific channel. These nonspecific channels allow cations—particularly Na+, K+, and Ca2+—to cross the membrane, but exclude anions.
Ion channels do not always freely allow ions to diffuse across the membrane. Some are opened by certain events, meaning the channels are gated, so another way that channels can be categorised is based on how they are gated. Although these classes of ion channels are found primarily in the cells of nervous or muscular tissue, they also can be found in the cells of epithelial and connective tissues.
A ligand-gated channel opens because a signalling molecule, a ligand, binds to the extracellular region of the channel. This type of channel is also known as an ionotropic receptor because when the ligand, known as a neurotransmitter in the nervous system, binds to the protein, ions cross the membrane changing its charge (Figure 7.14).
A mechanically gated channel opens because of a physical distortion of the cell membrane. Many channels associated with the sense of touch (somatosensation) are mechanically gated. For example, as pressure is applied to the skin, these channels open and allow ions to enter the cell. Similar to this type of channel would be the channel that opens based on temperature changes, as in testing the water in the shower (Figure 7.15).
A voltage-gated channel is a channel that responds to changes in the electrical properties of the membrane in which it is embedded. Normally, the inner portion of the membrane is at a negative voltage. When that voltage becomes less negative, the channel begins to allow ions to cross the membrane (Figure 7.16).
A leakage channel is randomly gated, meaning that it opens and closes at random, hence the reference to leaking. There is no actual event that opens the channel; instead, it has an intrinsic rate of switching between the open and closed states. Leakage channels contribute to the resting transmembrane voltage of the excitable membrane (Figure 7.17).
Resting membrane potential
A neuron at rest is negatively charged: the inside of a cell is approximately 70 millivolts more negative than the outside (−70 mV, note that this number varies by neuron type and by species). This voltage is called the resting membrane potential; it is caused by differences in the concentrations of ions inside and outside the cell. If the membrane were equally permeable to all ions, each type of ion would flow across the membrane and the system would reach equilibrium. Because ions cannot simply cross the membrane at will, there are different concentrations of several ions inside and outside the cell. The difference in the number of positively charged potassium ions (K+) inside and outside the cell dominates the resting membrane potential. When the membrane is at rest, K+ ions accumulate inside the cell due to a net movement with the concentration gradient. The negative resting membrane potential is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm). The negative charge within the cell is created by the cell membrane being more permeable to potassium ion movement than sodium ion movement. In neurons, potassium ions are maintained at high concentrations within the cell while sodium ions are maintained at high concentrations outside of the cell. The cell possesses potassium and sodium leakage channels that allow the two cations to diffuse down their concentration gradient. However, the neurons have far more potassium leakage channels than sodium leakage channels. Therefore, potassium diffuses out of the cell at a much faster rate than sodium leaks in. Because more cations are leaving the cell than are entering, this causes the interior of the cell to be negatively charged relative to the outside of the cell. The actions of the sodium-potassium pump help to maintain the resting potential, once established. Recall that sodium potassium pumps bring two K+ ions into the cell while removing three Na+ ions per ATP consumed. As more cations are expelled from the cell than taken in, the inside of the cell remains negatively charged relative to the extracellular fluid.
Dive deeper
Watch Osmosis by Elsevier (2016, December 1) Resting membrane potential – definition, examples [Youtube, 7:49mins]
The Action Potential
Resting membrane potential describes the steady state of the cell, which is a dynamic process that is balanced by ion leakage and ion pumping. Without any outside influence, it will not change. To get an electrical signal started, the membrane potential must change.
This starts with a channel opening for Na+ in the membrane. Because the concentration of Na+ is higher outside the cell than inside the cell by a factor of 10, ions will rush into the cell that are driven largely by the concentration gradient. Because sodium is a positively charged ion, it will change the relative voltage immediately inside the cell relative to immediately outside. The resting potential is the state of the membrane at a voltage of -70 mV, so the sodium cation entering the cell will cause it to become less negative. This is known as depolarisation, meaning the membrane potential moves toward zero.
The concentration gradient for Na+ is so strong that it will continue to enter the cell even after the membrane potential has become zero, so that the voltage immediately around the pore begins to become positive. The electrical gradient also plays a role, as negative proteins below the membrane attract the sodium ion. The membrane potential will reach +30 mV by the time sodium has entered the cell.
As the membrane potential reaches +30 mV, other voltage-gated channels are opening in the membrane. These channels are specific for the potassium ion. A concentration gradient acts on K+, as well. As K+ starts to leave the cell, taking a positive charge with it, the membrane potential begins to move back toward its resting voltage. This is called repolarisation, meaning that the membrane voltage moves back toward the -70mV value of the resting membrane potential.
Repolarisation returns the membrane potential to the -70mV value that indicates the resting potential, but it actually overshoots that value. Potassium ions reach equilibrium when the membrane voltage is below -70 mV, so a period of hyperpolarisation occurs while the K+ channels are open. Those K+ channels are slightly delayed in closing, accounting for this short overshoot.
What has been described here is the action potential, which is presented as a graph of voltage over time in Figure 7.19 It is the electrical signal that nervous tissue generates for communication. The change in the membrane voltage from -70 mV at rest to +30 mV at the end of depolarisation is a 100-mV change. That can also be written as a 0.1-V change. To put that value in perspective, think about a battery. An AA battery that you might find in a television remote has a voltage of 1.5 V, or a 9-V battery (the rectangular battery with two posts on one end) is, obviously, 9 V. The change seen in the action potential is one or two orders of magnitude less than the charge in these batteries. In fact, the membrane potential can be described as a battery. A charge is stored across the membrane that can be released under the correct conditions. A battery in your remote has stored a charge that is “released” when you push a button.
The question is, now, what initiates the action potential? The description above conveniently glosses over that point. But it is vital to understanding what is happening. The membrane potential will stay at the resting voltage until something changes. The description above just says that a Na+ channel opens. Now, to say “a channel opens” does not mean that one individual transmembrane protein changes. Instead, it means that one kind of channel opens. There are a few different types of channels that allow Na+ to cross the membrane. A ligand-gated Na+ channel will open when a neurotransmitter binds to it and a mechanically gated Na+ channel will open when a physical stimulus affects a sensory receptor (like pressure applied to the skin compresses a touch receptor). Whether it is a neurotransmitter binding to its receptor protein or a sensory stimulus activating a sensory receptor cell, some stimulus gets the process started. Sodium starts to enter the cell and the membrane becomes less negative.
A third type of channel that is an important part of depolarisation in the action potential is the voltage-gated Na+ channel. The channels that start depolarising the membrane because of a stimulus help the cell to depolarise from -70 mV to -55 mV. Once the membrane reaches that voltage, the voltage-gated Na+ channels open. This is what is known as the threshold. Any depolarisation that does not change the membrane potential to -55 mV or higher will not reach threshold and thus will not result in an action potential. Also, any stimulus that depolarises the membrane to -55 mV or beyond will cause a large number of channels to open and an action potential will be initiated.
Because of the threshold, the action potential can be likened to a digital event—it either happens or it does not. If the threshold is not reached, then no action potential occurs. If depolarisation reaches -55 mV, then the action potential continues and runs all the way to +30 mV, at which K+ causes repolarisation, including the hyperpolarising overshoot. Also, those changes are the same for every action potential, which means that once the threshold is reached, the exact same thing happens. A stronger stimulus, which might depolarise the membrane well past threshold, will not make a “bigger” action potential. Action potentials are “all or none.” Either the membrane reaches the threshold and everything occurs as described above, or the membrane does not reach the threshold and nothing else happens. All action potentials peak at the same voltage (+30 mV), so one action potential is not bigger than another. Stronger stimuli will initiate multiple action potentials more quickly, but the individual signals are not bigger.
For example
You will not feel a greater sensation of pain, or have a stronger muscle contraction, because of the size of the action potential because they are not different sizes.
As we have seen, the depolarisation and repolarisation of an action potential are dependent on two types of channels (the voltage-gated Na+ channel and the voltage-gated K+ channel). The voltage-gated Na+ channel actually has two gates. One is the activation gate, which opens when the membrane potential crosses -55 mV. The other gate is the inactivation gate, which closes after a specific period of time—on the order of a fraction of a millisecond. When a cell is at rest, the activation gate is closed, and the inactivation gate is open. However, when the threshold is reached, the activation gate opens, allowing Na+ to rush into the cell. Timed with the peak of depolarisation, the inactivation gate closes. During repolarisation, no more sodium can enter the cell. When the membrane potential passes -55 mV again, the activation gate closes. After that, the inactivation gate re-opens, making the channel ready to start the whole process over again.
The voltage-gated K+ channel has only one gate, which is sensitive to a membrane voltage of -50 mV. However, it does not open as quickly as the voltage-gated Na+ channel does. It might take a fraction of a millisecond for the channel to open once that voltage has been reached. The timing of this coincides exactly with when the Na+ flow peaks, so voltage-gated K+ channels open just as the voltage-gated Na+ channels are being inactivated. As the membrane potential repolarises and the voltage passes -50 mV again, the channel closes—again, with a little delay. Potassium continues to leave the cell for a short while and the membrane potential becomes more negative, resulting in the hyperpolarising overshoot. Then the channel closes again, and the membrane can return to the resting potential because of the ongoing activity of the non-gated channels and the Na+ /K+ pump.
All of this takes place within approximately two milliseconds (Figure 7.20). While an action potential is in progress, another one cannot be initiated. That effect is referred to as the refractory period. There are two phases of the refractory period: the absolute refractory period and the relative refractory period. During the absolute phase, another action potential will not start. This is because of the inactivation gate of the voltage-gated Na+ channel. Once that channel is back to its resting conformation (less than -55 mV), a new action potential could be started, but only by a stronger stimulus than the one that initiated the current action potential. This is because of the flow of K+ out of the cell. Because that ion is rushing out, any Na+ that tries to enter will not depolarise the cell but will only keep the cell from hyperpolarising.
Propagation of the Action Potential
The action potential is initiated at the beginning of the axon, at what is called the initial segment. There is a high density of voltage-gated Na+ channels so that rapid depolarisation can take place here. Going down the length of the axon, the action potential is propagated because more voltage-gated Na+ channels are opened as the depolarisation spreads. This spreading occurs because Na+ enters through the channel and moves along the inside of the cell membrane. As the Na+ moves, or flows, a short distance along the cell membrane, its positive charge depolarises a little more of the cell membrane. As that depolarisation spreads, new voltage-gated Na+ channels open and more ions rush into the cell, spreading the depolarisation a little farther.
Because voltage-gated Na+ channels are inactivated at the peak of the depolarisation, they cannot be opened again for a brief time—the absolute refractory period. Because of this, depolarisation spreading back toward previously opened channels has no effect. The action potential must propagate toward the axon terminals; as a result, the polarity of the neuron is maintained, as mentioned above.
Propagation, as described above, applies to unmyelinated axons. When myelination is present, the action potential propagates differently. Sodium ions that enter the cell at the initial segment start to spread along the length of the axon segment, but there are no voltage-gated Na+ channels until the first node of Ranvier. Because there is not constant opening of these channels along the axon segment, the depolarisation spreads at an optimal speed. The distance between nodes is the optimal distance to keep the membrane still depolarised above threshold at the next node. As Na+ spreads along the inside of the membrane of the axon segment, the charge starts to dissipate. If the node were any farther down the axon, that depolarisation would have fallen off too much for voltage-gated Na+ channels to be activated at the next node of Ranvier. If the nodes were any closer together, the speed of propagation would be slower.
Propagation along an unmyelinated axon is referred to as continuous conduction; along the length of a myelinated axon, it is saltatory conduction. Continuous conduction is slow because there are always voltage-gated Na+ channels opening, and more and more Na+ is rushing into the cell. Saltatory conduction is faster because the action potential basically jumps from one node to the next (saltare = “to leap”), and the new influx of Na+ renews the depolarised membrane. Along with the myelination of the axon, the diameter of the axon can influence the speed of conduction. Much as water runs faster in a wide river than in a narrow creek, Na+ -based depolarisation spreads faster down a wide axon than down a narrow one. This concept is known as resistance and is generally true for electrical wires or plumbing, just as it is true for axons, although the specific conditions are different at the scales of electrons or ions versus water in a river.
Dive deeper 2-Minute Neuroscience: Action Potential (July 2014) [YouTube, 2:01mins]
Case study
A 5-year-old male Labrador, Hunter, presented following recurrent fits and unusual behavioural episodes. These episodes included sudden collapse, muscle twitching, and brief periods of disorientation. Neurological examination and diagnostic testing ruled out metabolic and structural causes, leading to a diagnosis of idiopathic epilepsy—a condition where seizures occur without an identifiable underlying cause. These seizures result from abnormal electrical activity in the brain, disrupting normal signalling pathways.
Medical management was initiated with anticonvulsant therapy to stabilise neuronal activity and reduce seizure frequency. Ongoing monitoring and owner education are essential to ensure effective control and maintain Hunter’s quality of life.
Other neurological signs of nerve conduction disorders can also include impaired vision, muscle twitching, circling, incoordination, paralysis, weakness, abnormal gait, difficulty chewing or swallowing, seizures, head pressing, head tilt, and behavioural changes.
Section Review
The nervous system is characterised by electrical signals that are sent from one area to another. Whether those areas are close or very far apart, the signal must travel along an axon. The basis of the electrical signal is the controlled distribution of ions across the membrane. Transmembrane ion channels regulate when ions can move in or out of the cell, so that a precise signal is generated. This signal is the action potential which has a very characteristic shape based on voltage changes across the membrane in a given time period.
The membrane is normally at rest with established Na+ and K+ concentrations on either side. A stimulus will start the depolarisation of the membrane, and voltage-gated channels will result in further depolarisation followed by repolarisation of the membrane. A slight overshoot of hyperpolarisation marks the end of the action potential. While an action potential is in progress, another cannot be generated under the same conditions. While the voltage-gated Na+ channel is inactivated, absolutely no action potentials can be generated. Once that channel has returned to its resting state, a new action potential is possible, but it must be started by a relatively stronger stimulus to overcome the K+ leaving the cell.
The action potential travels down the axon as voltage-gated ion channels are opened by the spreading depolarisation. In unmyelinated axons, this happens in a continuous fashion because there are voltage-gated channels throughout the membrane. In myelinated axons, propagation is described as saltatory because voltage-gated channels are only found at the nodes of Ranvier and the electrical events seem to “jump” from one node to the next. Saltatory conduction is faster than continuous conduction, meaning that myelinated axons propagate their signals faster. The diameter of the axon also makes a difference as ions diffusing within the cell have less resistance in a wider space.
Review Questions
Critical Thinking Questions
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